This proposal is dedicated to 1), establishing the efficacy of vitamin D for colorectal cancer (CRC) chemoprevention in humans; and 2), identifying the vitamin D congener most efficacious for CRC chemoprevention. Animal studies indicate that the active metabolite of vitamin D 1,25(OH)2D3 reduces the number and size of colon cancers; while epidemiological data show an inverse relationship between vitamin D intake and CRC risk. However 1,25(OH)2D3 causes hypercalcemia. We therefore synthesized a novel vitamin D analog, 11-hydroxy-24-ethyl-cholecalciferol [11(OH)D5]. In our preliminary data we show that this novel compound is non-toxic yet decreases the formation of aberrant crypt foci (ACF) by 85% in mice exposed to the carcinogen azoxymethane (AOM). We have recently demonstrated that cyp27A1 [required to convert cholecalciferol to 25(OH)D3] as well as cyp27B1 [required to convert 25(OH)D3 to 1,25(OH)2D3] are present in epithelial cells lining the normal human colon. This suggests that non-toxic and widely available cholecalciferol may be sufficient to prevent CRC. However, the CRC chemopreventive efficacy of cholecalciferol has not been assessed in humans; nor has the efficacy of this drug been assessed in comparison to 25(OH)D3, 1,25(OH)2D3, or to our novel drug 11(OH)D5. Chemoprevention studies typically use colonic adenomas as a CRC biomarker. Yet adenomas are relatively fixed lesions such that studies using them as a biomarker require years and large numbers of patients to complete. In contrast, we use magnification chromo-colonoscopy (MCC) for CRC screening, allowing us to routinely enumerate ACF number in humans. Since ACF are more fluid lesions that are present in greater numbers than adenomas, ACF are increasingly used as a surrogate CRC marker. Our hypothesis is that activation of the vitamin D receptor early in the process of CRC malignant transformation can prevent or attenuate tumor progression. Our aims are to: 1), establish the efficacy of vitamin D for CRC chemoprevention by evaluating the ability of cholecalciferol to reduce ACF's in humans; and 2), compare this with 25(OH)D3, 1,25(OH)2D3 and our novel drug 11(OH)D5 in mice exposed to AOM. Overall these studies will allow us to definitively determine the suitability of vitamin D in CRC chemoprevention, as well as assess the relative efficacy of a novel non-calcemic vitamin D analog for CRC chemoprevention. Colorectal cancer (CRC) is the second most common malignancy in men and women in the United States. Although vitamin D has been suspected to prevent CRC for nearly 30 years, it has never been directly evaluated in humans. Typically CRC chemoprevention studies use colonic adenomas as a biomarker, but these studies require hundreds to thousands of patients, and take years to complete. In contrast, aberrant crypt foci (ACF), the earliest histopathological lesions associated with malignant transformation in the colon, are more prevalent and are more fluid than adenomas. Hence this proposal is dedicated to assessing known and novel vitamin D analogs for their CRC chemopreventative efficacy using alteration in ACF number as our primary end-point.